This invention relates to bioreactor systems and to the fluid processing components used in such systems.
Bioreactor systems are increasingly being used for the synthesis of biological products. An exemplary bioreactor system employs a hollow fiber bioreactor cartridge having a multitude of semipermeable fibers that serve as a support and a nutrient conduit for cell culture. Cells are typically grown on the outside of the semipermeable fibers and are maintained by perfusion of nutrient medium which is circulated within the fibers. Waste products excreted by the cultured cells perfuse into the fibers and are carried away in the nutrient medium. Desirable cellular by-products, such as monoclonal antibodies, are typically too large to perfuse into the fibers and are thus trapped in the extracapillary region of the bioreactor cartridge.
The process control tasks associated with operation of a bioreactor system are very demanding. In many applications, the desired cell by-products are produced at an extremely slow rate. Sometimes the system must operate continuouly for weeks or months at a time in order to accumulate a fraction of a gram of usable product. Any malfunction in the system can have long lasting repercussions on a project. Accordingly, it is crucial that all process control components be able to work continuously and reliably for extended periods of time with a minimum of human supervision and intervention.
The reliability of prior art bioreactors suffers by reason of the complex subsystems typically incorporated therein. An exemplary system may include a large incubator and three or more pumps. One pump is used to circulate nutrient fluid from a reservoir through the bioreactor. A second pump is used to add fresh nutrient fluid to the reservoir. A third pump is used to remove spent nutrient fluid from the reservoir. A fourth pump is used to circulate a warm water bath which surrounds the nutrient fluid reservoir. Such complicated systems are inherently susceptible to reliability problems when operated over extended periods of time.
Related to the reliability concern is that of maintaining absolute sterility. The introduction of virtually any foreign body into the system will fatally disrupt its operation. Accordingly, it is desirable that bioreactor design be oriented so as to minimize opportunities for the system to become contaminated.
One contaminant that has been unavoidable in prior art hollow fiber bioreactor systems has been the plasticizer put in the hollow fiber cartridges by their manufacturers. The semipermeable fibers of which these cartridges are comprised tend to dry out and become brittle if exposed to air. Accordingly, manufacturers coat the inside of the fibers with a plasticizer material, such as glycerin, before shipping the product. A large cartridge may contain as much as 100 milliliters of this material.
When the cartridge is received by a user, there is no practical technique for removing the plasticizer without jeopardizing the sterility of the cartridge. If the cartridge does become contaminated, it must be discarded, for it cannot tolerate a sterilization process due to the delicate nature of the semipermeable fibers.
In the prior art, the issue of the plasticizer has been ignored. Cartridges have simply been installed in systems with the plasticizer intact. This material is eventually flushed from the fibers by circulation of the nutrient fluid and ends up floating in the nutrient fluid reservoir as a greasy mass. Although sterile, this contaminant nonetheless interferes with proper operation of delicate bioreactor systems.
Accordingly, a need remains for a method and apparatus for removing plasticizer from bioreactor systems.